DNA polymorphisms in ITPA including basis of inosine triphosphatase deficiency.

Intracellular concentrations of the nucleotide inosine triphosphate (ITP) are regulated by ITP-ase (EC 3.6.1.

Polymorphisms in the gene encoding phosphatidylserine-specific phospholipase A1 ( PSPLA1).

We report the identification of nine DNA polymorphisms in PSPLA1 encoding phosphatidylserine-specific phospholipase A1. Because the gene product shares homology with triglyceride lipases, these polymorphisms may be useful in association studies with metabolic traits such as hypertriglyceridemia and related lipoprotein abnormalities, and will also provide tools for mapping studies of chromosome 3q13.13-13.

Gene-drug interaction: additive influence of mutant APOA1 and testosterone on plasma HDL-cholesterol.

Objectives: Factors associated with decreased plasma high-density lipoprotein (HDL) cholesterol concentration, or hypoalphalipoproteinemia, include androgenic steroids and mutations in APOA1, encoding apolipoprotein (apo) A-I, the main structural protein of HDL. However, there is little information regarding the extent of plasma HDL lowering when exogenous testosterone is used in subjects with monogenic low HDL.

Design And Methods: A man with coronary heart disease (CHD) had been receiving exogenous testosterone post-orchidectomy.

Functional promoter polymorphism in SREBP cleavage-activating protein (SCAP).

We report the identification of a loss-of-function -11C>T promoter mutation in the gene encoding the sterol regulatory element binding protein cleavage-activating protein (SCAP). The -11T allele was associated with a marked reduction in promoter activity in a luciferase-based expression system. We also report additional common single-nucleotide polymorphisms in the SCAP promoter and coding sequence that were identified by using direct sequencing to screen the genomic DNA of subjects with combined hyperlipidemia.

Identification of polymorphisms in the human SHP1 gene.

Because mutations in human SHP1 underlie obesity and diabetes, SHP1 is a candidate gene for human lipodystrophy syndromes. To identify possible disease mutations and/or common single-nucleotide polymorphisms (SNPs), we developed primer pairs to amplify the promoter and coding region of SHP1. We used these pairs to sequence SHP1 in lipodystrophy patients who had no mutations in known lipodystrophy genes, and also in normal control subjects.

Functional linkage between the endoplasmic reticulum protein Hsp47 and procollagen expression in human vascular smooth muscle cells.

Hsp47 is a heat stress protein that interacts with procollagen in the lumen of the endoplasmic reticulum, which is vital for collagen elaboration and embryonic viability. The precise actions of Hsp47 remain unclear, however. To evaluate the effects of Hsp47 on collagen production we infected human vascular smooth muscle cells (SMCs) with a retrovirus containing Hsp47 cDNA.

Identification of single-nucleotide polymorphisms in the human LPIN1 gene.

Because mutations in the murine analog of human LPIN1 cause lipodystrophy in mice, LPIN1 is a candidate gene for human lipodystrophy syndromes. To identify possible disease mutations and/or common single-nucleotide polymorphisms (SNPs), we developed primer pairs to amplify the 21 exons of LPIN1. We used these primer pairs to sequence LPIN1 in lipodystrophy patients who had no mutations in known lipodystrophy genes, and also in normal control subjects.

The molecular basis of genetic lipodystrophies.

Objectives: Hyperinsulinemia is often associated with a cluster of metabolic abnormalities, which usually presents before the onset of frank diabetes. Lipodystrophy syndromes are frequently associated with hyperinsulinemia and may act as models for insulin resistance. Lipodystrophy is characterized in broad terms by loss of subcutaneous adipose tissue.

Cardiomyopathy in congenital complete lipodystrophy.

Molecular genetic studies have pointed to a relationship between congenital lipodystrophy syndromes and some cardiac disorders. For instance, mutations in LMNA cause either lipodystrophy or cardiomyopathy, indicating that different mutations in the same gene can produce these clinical syndromes. The present authors describe a 10-year-old female with Berardinelli-Seip congenital complete lipodystrophy (MIM 606158) caused by homozygosity for a frameshift mutation in BSCL2.

Successful pregnancy outcome in a patient with severe chylomicronemia due to compound heterozygosity for mutant lipoprotein lipase.

Objectives: Familial chylomicronemia syndrome is characterized by massive accumulation of plasma chylomicrons, which typically results from an absolute deficiency of lipoprotein lipase (LPL). Chylomicronemia in pregnancy is a rare, but serious clinical problem and can be found in patients with underlying molecular defects in the LPL gene. We report the course and treatment of an 18 yr-old primigravida who had LPL deficiency and hypertriglyceridemia since birth.

Acanthocytosis in a patient with homozygous familial hypobetalipoproteinemia due to a novel APOB splice site mutation.

We report on acanthocytosis in a 31-year-old woman with homozygous familial hypobetalipoproteinemia due to a mutation affecting the splicing of the APOB gene encoding apolipoprotein B. Treatment with fat-soluble vitamins was associated with arrest of the usually progressive neurological complications of this condition. However, the acanthocytosis - literally 'thorny' erythrocytes that result from abnormal membrane fluidity - persists despite treatment.

A BRCA1 mutation in Native North American families.

Germline mutations in the BRCA1 (MIM 113705) and BRCA2 (MIM 600185) genes have been identified for breast and ovarian cancer families of diverse ethnic backgrounds. To date, there have been no reports of Native North American families with mutations in BRCA1 or BRCA2. Here we report two families of aboriginal descent both with the same BRCA1 alterations (1510insG, 1506A>G).

Environmental modulation of atherosclerosis end points in familial hypercholesterolemia.

In familial hypercholesterolemia (FH), early coronary heart disease (CHD) is a complex trait that results from a large monogenic component of susceptibility due to elevated LDL cholesterol. This was demonstrated by observation of the high risk of early CHD in FH subjects compared with the general population. However, not all subjects with a LDLR gene mutation suffer with early CHD.

Association of parity with risk of type 2 diabetes and related metabolic disorders.

Objective: The relationship between parity and risk of diabetes is controversial, and little information is available regarding associations between parity and measures of insulin resistance and beta-cell function. The objective of this study was to investigate the association between parity and risk of glucose intolerance and related metabolic disorders using data from a population-based study in a Native Canadian community.

Research Design And Methods: Female participants (n = 383, aged 12-79 years) provided fasting blood samples for the determination of glucose, insulin, C-peptide, and proinsulin concentrations.

HNF-1alpha G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community.

The prevalence of type 2 diabetes mellitus in the Oji-Cree of northwestern Ontario is the third highest in the world. A private mutation, G319S, in HNF1A, which encodes hepatic nuclear factor-1alpha (HNF-1alpha), was associated with Oji-Cree type 2 diabetes and was found in approximately 40% of affected subjects. The G319S mutation reduced the in vitro ability of HNF-1alpha to activate transcription by approximately 50%, with no effect on DNA binding or protein stability.

Association of a single nucleotide polymorphism in CPB2 encoding the thrombin-activable fibrinolysis inhibitor (TAF1) with blood pressure.

Thrombin-activable fibrinolysis inhibitor (TAFI) is a hepatically secreted zymogen, whose substrates include bradykinin. The CPB2 gene encoding TAFI is a candidate gene for blood pressure. A recently identified single nucleotide polymorphism (SNP) in the CPB2 coding region, designated as 1057C > T, results in an amino acid change at TAFI residue 325 (Ile > Thr325).

Beta blockers normalize QT hysteresis in long QT syndrome.

Objectives: This study was performed to evaluate the impact of beta blockers on QT adaptation to heart rate during the exercise and recovery phases of exercise testing in long QT syndrome.

Background: Long QT syndrome is characterized by familial syncope and sudden death in the context of sudden heart rate changes. QT hysteresis has been proposed as a phenotypic marker of long QT syndrome, suggesting altered QT adaptation to changes in heart rate.

A single nucleotide polymorphism in protein tyrosine phosphatase PTP-1B is associated with protection from diabetes or impaired glucose tolerance in Oji-Cree.

Several lines of evidence support a role for protein tyrosine phosphatase 1B (PTP-1B) in metabolism, and specifically in insulin sensitivity and obesity. We report the development of reagents for the amplification and sequencing of the PTP-1B gene, which has resulted in the identification of a novel single nucleotide polymorphism (SNP), designated 981C-->T. We found a significant association between this SNP and the risk of either impaired glucose tolerance (IGT) or type 2 diabetes in the Oji-Cree of Sandy Lake, Ontario, Canada.

Cross-sectional and prospective associations between abdominal adiposity and proinsulin concentration.

The objective of this study was to investigate the associations of total and abdominal obesity with variation in proinsulin concentration in a Native Canadian population experiencing an epidemic of type 2 diabetes mellitus (DM). Between 1993 and 1995, 728 members of a Native Canadian community participated in a population-based survey to determine the prevalence and risk factors for type 2 DM. Samples for glucose, C-peptide, and proinsulin were drawn after an overnight fast, and a 75-g oral glucose tolerance test was administered.

Single-nucleotide polymorphisms of the proprotein convertase subtilisin/ kexin type 5 (PCSK5) gene.

The proprotein convertase. subtilisin/kexin type 5, or PCSK5, mediates post-translational endoproteolytic processing for several integrin alpha subunits. We identified two silent single-nucleotide polymorphisms (SNPs) in PCSK5, which were found to vary in frequency across ethnic groups.

ABCC6 gene polymorphism associated with variation in plasma lipoproteins.

The ATP cassette-binding (ABC) gene superfamily contains more than 40 members, many of which are involved in cellular lipid transport. The most prominent example is ABCA1, mutations in which affect plasma high-density lipoprotein (HDL) cholesterol concentration. ABCC6 is another member of the ABC gene family, and mutations in ABCC6 were recently shown to cause pseudoxanthoma elasticum (PXE).

Transforming growth factor-beta1 inhibits macrophage cholesteryl ester accumulation induced by native and oxidized VLDL remnants.

Transforming growth factor beta1 (TGF-beta1) is secreted by various cells, including macrophages, smooth muscle cells, and endothelial cells. TGF-beta1 is present in atherosclerotic lesions, but its role in regulating macrophage foam cell formation is not understood. Hypertriglyceridemic very low density lipoprotein (VLDL) remnants (VLDL-REMs) in their native or oxidized form will induce cholesteryl ester (CE) and triglyceride (TG) accumulation in macrophages.